Applications of Cancer Cell-Specific Aptamers in Targeted Delivery of Anticancer Therapeutic Agents

Aptamers are single-stranded oligonucleotides that specifically bind and interact with their corresponding targets, including proteins and cells, through unique three-dimensional structures. Numerous aptamers have been developed to target cancer biomarkers with high specificity and affinity, and some are employed as versatile guiding ligands for cancer-specific drug delivery and anti-cancer therapeutics. In this review, we list the aptamers that target tumor surface biomarkers and summarize the representative applications of aptamers as agonists and antagonists that activate anti-cancer and inactivate pro-cancer biomarkers, respectively. In addition, we describe applications of aptamer-drug or aptamer-oligonucleotide conjugates that can deliver therapeutic agents, including small interfering RNAs, micro RNAs, short hairpin RNAs, and chemotherapeutic molecules, to cancer cells. Moreover, we provide examples of aptamer- conjugated nano-vehicles, in which cancer-targeting oligonucleotide aptamers are conjugated with nano-vehicles such as liposomes, micelles, polymeric nanoparticles, and quantum dots. Conjugation of aptamers with anti-cancer drugs and nano-vehicles will facilitate innovative applications of aptamer-based cancer therapeutics.

[1]  A. Hovanessian,et al.  Surface Expressed Nucleolin Is Constantly Induced in Tumor Cells to Mediate Calcium-Dependent Ligand Internalization , 2010, PloS one.

[2]  W. Tan,et al.  Automated Modular Synthesis of Aptamer–Drug Conjugates for Targeted Drug Delivery , 2014, Journal of the American Chemical Society.

[3]  U. Nielsen,et al.  Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. , 2006, Cancer research.

[4]  Robert Langer,et al.  Nanotechnology in drug delivery and tissue engineering: from discovery to applications. , 2010, Nano letters.

[5]  Koji Sode,et al.  Screening and Improvement of an Anti-VEGF DNA Aptamer , 2010, Molecules.

[6]  J. Szostak,et al.  In vitro selection of RNA molecules that bind specific ligands , 1990, Nature.

[7]  Anton P. McCaffrey,et al.  Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors , 2009, Nature Biotechnology.

[8]  D. S. Coffey,et al.  Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. , 2002, Cancer research.

[9]  Lawrence A. Yannuzzi,et al.  PRECLINICAL AND PHASE 1A CLINICAL EVALUATION OF AN ANTI-VEGF PEGYLATED APTAMER (EYE001) FOR THE TREATMENT OF EXUDATIVE AGE-RELATED MACULAR DEGENERATION , 2002, Retina.

[10]  S. De Flora,et al.  Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention , 2010, Journal of the National Cancer Institute.

[11]  T. Allen,et al.  Ligand-targeted liposomal anticancer drugs. , 2003, Progress in lipid research.

[12]  Jørgen Kjems,et al.  Characterisation of aptamer–target interactions by branched selection and high-throughput sequencing of SELEX pools , 2015, Nucleic acids research.

[13]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[14]  W. Duan,et al.  Selection of DNA aptamers against epithelial cell adhesion molecule for cancer cell imaging and circulating tumor cell capture. , 2013, Analytical chemistry.

[15]  Kemin Wang,et al.  Selection of aptamers for molecular recognition and characterization of cancer cells. , 2007, Analytical chemistry.

[16]  Koichi Abe,et al.  Affinity improvement of a VEGF aptamer by in silico maturation for a sensitive VEGF-detection system. , 2013, Analytical chemistry.

[17]  Robert Langer,et al.  Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy , 2010, Proceedings of the National Academy of Sciences.

[18]  Xin Lu,et al.  Novel MUC1 Aptamer Selectively Delivers Cytotoxic Agent to Cancer Cells In Vitro , 2012, PloS one.

[19]  C H Heldin,et al.  Inhibitory DNA ligands to platelet-derived growth factor B-chain. , 1996, Biochemistry.

[20]  A. Debrabant,et al.  Aptamer Based, Non-PCR, Non-Serological Detection of Chagas Disease Biomarkers in Trypanosoma cruzi Infected Mice , 2014, PLoS neglected tropical diseases.

[21]  C. Ferreira,et al.  DNA Aptamers That Bind to MUC1 Tumour Marker: Design and Characterization of MUC1-Binding Single-Stranded DNA Aptamers , 2006, Tumor Biology.

[22]  Srinivasan Ramachandran,et al.  In silico selection of an aptamer to estrogen receptor alpha using computational docking employing estrogen response elements as aptamer-alike molecules , 2016, Scientific Reports.

[23]  C. Sawyers.  The cancer biomarker problem , 2008, Nature.

[24]  You Han Bae,et al.  Tumor heterogeneity and its implication for drug delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[25]  Kinam Park,et al.  Targeted drug delivery to tumors: myths, reality and possibility. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[26]  Theresa M Allen,et al.  Internalizing antibodies are necessary for improved therapeutic efficacy of antibody-targeted liposomal drugs. , 2002, Cancer research.

[27]  Paula J. Bates,et al.  AGRO100 inhibits activation of nuclear factor-κB (NF-κB) by forming a complex with NF-κB essential modulator (NEMO) and nucleolin , 2006, Molecular Cancer Therapeutics.

[28]  Weihong Tan,et al.  Aptamer-modified gold nanoparticles for colorimetric determination of platelet-derived growth factors and their receptors. , 2005, Analytical chemistry.

[29]  Chad A Mirkin,et al.  Gold nanoparticles for biology and medicine. , 2010, Angewandte Chemie.

[30]  Walhan Alshaer,et al.  Functionalizing Liposomes with anti-CD44 Aptamer for Selective Targeting of Cancer Cells. , 2015, Bioconjugate chemistry.

[31]  D. Josić,et al.  Mammalian plasma membrane proteins as potential biomarkers and drug targets , 2011, Electrophoresis.

[32]  J. Wengel,et al.  By-Product Formation in Repetitive PCR Amplification of DNA Libraries during SELEX , 2014, PloS one.

[33]  Jun‐Jie Zhu,et al.  Versatile aptasensor for electrochemical quantification of cell surface glycan and naked-eye tracking glycolytic inhibition in living cells. , 2017, Biosensors & bioelectronics.

[34]  T. Zhang,et al.  Liposome-anchored vascular endothelial growth factor aptamers. , 1998, Bioconjugate chemistry.

[35]  Daniel Agudelo,et al.  Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: structural features and biological implications. , 2014, International journal of biological macromolecules.

[36]  M. Stone,et al.  In silico selection of RNA aptamers , 2009, Nucleic acids research.

[37]  A. Pardi,et al.  A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Robert M Hoffman,et al.  The challenges posed by cancer heterogeneity , 2012, Nature Biotechnology.

[39]  Dongsheng Liu,et al.  DNA origami/gold nanorod hybrid nanostructures for the circumvention of drug resistance. , 2017, Nanoscale.

[40]  B. Ristau,et al.  The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of research. , 2014, Urologic oncology.

[41]  Avraham Rasooly,et al.  Self-Assembled DNA Generated Electric Current Biosensor for HER2 Analysis. , 2017, Analytical chemistry.

[42]  J. Burnett,et al.  Dual functional BAFF receptor aptamers inhibit ligand-induced proliferation and deliver siRNAs to NHL cells , 2013, Nucleic acids research.

[43]  C. Esposito,et al.  Selective delivery of therapeutic single strand antimiRs by aptamer-based conjugates. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[44]  Robert Langer,et al.  Quantum dot-aptamer conjugates for synchronous cancer imaging, therapy, and sensing of drug delivery based on bi-fluorescence resonance energy transfer. , 2007, Nano letters.

[45]  Weihong Tan,et al.  Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications. , 2013, Journal of the American Chemical Society.

[46]  Bertrand Tavitian,et al.  Comparison of different strategies to select aptamers against a transmembrane protein target. , 2006, Oligonucleotides.

[47]  Jie Gao,et al.  PLGA nanoparticles with CD133 aptamers for targeted delivery and sustained release of propranolol to hemangioma. , 2017, Nanomedicine.

[48]  Y. Assaraf,et al.  Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. , 2011, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[49]  John C. Chaput,et al.  Analysis of aptamer discovery and technology , 2017 .

[50]  Hideo Akiyama,et al.  Intraocular injection of an aptamer that binds PDGF‐B: A potential treatment for proliferative retinopathies , 2006, Journal of cellular physiology.

[51]  Cuichen Wu,et al.  Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy. , 2013, Journal of the American Chemical Society.

[52]  Weihong Tan,et al.  Generating aptamers for recognition of virus-infected cells. , 2009, Clinical chemistry.

[53]  S. Jayasena.  Aptamers: an emerging class of molecules that rival antibodies in diagnostics. , 1999, Clinical chemistry.

[54]  Xiaohong Fang,et al.  Aptamers generated from cell-SELEX for molecular medicine: a chemical biology approach. , 2010, Accounts of chemical research.

[55]  Jeff Zimmerman,et al.  Crystal structure of NF-κB (p50)2 complexed to a high-affinity RNA aptamer , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[56]  C. Benz,et al.  Development of ligand-targeted liposomes for cancer therapy , 2004, Expert opinion on therapeutic targets.

[57]  J. Rossi,et al.  Current Advances in Aptamers for Cancer Diagnosis and Therapy , 2018, Cancers.

[58]  Q. Yao,et al.  Targeted drug delivery in pancreatic cancer. , 2010, Biochimica et biophysica acta.

[59]  M. Junttila,et al.  Influence of tumour micro-environment heterogeneity on therapeutic response , 2013, Nature.

[60]  Xiaoling Zhang,et al.  Molecular Assembly of an Aptamer–Drug Conjugate for Targeted Drug Delivery to Tumor Cells , 2009, Chembiochem : a European journal of chemical biology.

[61]  J. Dannenberg,et al.  Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. , 2012, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[62]  Y. Zu,et al.  A unique aptamer-drug conjugate for targeted therapy of multiple myeloma , 2016, Leukemia.

[63]  H. Kourlas,et al.  Pegaptanib sodium for the treatment of neovascular age-related macular degeneration: a review. , 2006, Clinical therapeutics.

[64]  P. Bouvet,et al.  AS-1411, a guanosine-rich oligonucleotide aptamer targeting nucleolin for the potential treatment of cancer, including acute myeloid leukemia. , 2010, Current opinion in molecular therapeutics.

[65]  Y. Zu,et al.  Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy , 2014, Molecular therapy. Nucleic acids.

[66]  E. Spicer,et al.  The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells. , 2008, Cancer research.

[67]  Yong-mei Song,et al.  Novel HER2 Aptamer Selectively Delivers Cytotoxic Drug to HER2-positive Breast Cancer Cells in Vitro , 2012, Journal of Translational Medicine.

[68]  T. Lybrand,et al.  Evoking picomolar binding in RNA by a single phosphorodithioate linkage , 2016, Nucleic acids research.

[69]  S. M. Taghdisi,et al.  Double targeting and aptamer-assisted controlled release delivery of epirubicin to cancer cells by aptamers-based dendrimer in vitro and in vivo. , 2016, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[70]  Y. Jeong,et al.  A drug-loaded aptamer-gold nanoparticle bioconjugate for combined CT imaging and therapy of prostate cancer. , 2010, ACS nano.

[71]  B. Sullenger,et al.  Identification and Characterization of an Agonistic Aptamer Against the T Cell Costimulatory Receptor, OX40 , 2022 .

[72]  D. Richel,et al.  The developing cancer stem-cell model: clinical challenges and opportunities. , 2012, The Lancet. Oncology.

[73]  Hui Chen,et al.  Molecular recognition of acute myeloid leukemia using aptamers , 2008, Leukemia.

[74]  Zong-Hong Lin,et al.  Aptamer-modified gold nanoparticles for targeting breast cancer cells through light scattering , 2009 .

[75]  Xi‐lin Xiao,et al.  A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy , 2015, PloS one.

[76]  G. Mayer,et al.  Molecular mechanism for inhibition of g protein-coupled receptor kinase 2 by a selective RNA aptamer. , 2012, Structure.

[77]  Weihong Tan,et al.  DNA aptamer–micelle as an efficient detection/delivery vehicle toward cancer cells , 2009, Proceedings of the National Academy of Sciences.

[78]  J. McNamara,et al.  Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. , 2008, The Journal of clinical investigation.

[79]  Chao Liang,et al.  Development of Cell-SELEX Technology and Its Application in Cancer Diagnosis and Therapy , 2016, International journal of molecular sciences.

[80]  B. Chabner,et al.  Chemotherapy and the war on cancer , 2005, Nature Reviews Cancer.

[81]  Dong-Eun Kim,et al.  Comparison of Drug Delivery Efficiency between Doxorubicin Intercalated in RNA Aptamer and One Encapsulated in RNA Aptamer- Conjugated Liposome , 2015 .

[82]  J. Katzenellenbogen,et al.  Selective Delivery of an Anticancer Drug with Aptamer-Functionalized Liposomes to Breast Cancer Cells in Vitro and in Vivo. , 2013, Journal of materials chemistry. B.

[83]  Weian Zhao,et al.  A polyvalent aptamer system for targeted drug delivery. , 2013, Biomaterials.

[84]  B. Sullenger,et al.  Assembling OX40 aptamers on a molecular scaffold to create a receptor-activating aptamer. , 2008, Chemistry & biology.

[85]  James O McNamara,et al.  Cell-internalization SELEX: method for identifying cell-internalizing RNA aptamers for delivering siRNAs to target cells. , 2015, Methods in molecular biology.

[86]  John J. Rossi,et al.  Cell-type-specific, Aptamer-functionalized Agents for Targeted Disease Therapy , 2014, Molecular therapy. Nucleic acids.

[87]  Yi Lu,et al.  Reversible cell-specific drug delivery with aptamer-functionalized liposomes. , 2009, Angewandte Chemie.

[88]  M. Gu,et al.  Advances in aptamer screening and small molecule aptasensors. , 2014, Advances in biochemical engineering/biotechnology.

[89]  S. Rottenberg,et al.  New tools for old drugs: Functional genetic screens to optimize current chemotherapy , 2018, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[90]  C. Ban,et al.  Dual aptamer-functionalized silica nanoparticles for the highly sensitive detection of breast cancer. , 2015, Biosensors & bioelectronics.

[91]  Chen Wang,et al.  Novel Aptamer-Nanoparticle Bioconjugates Enhances Delivery of Anticancer Drug to MUC1-Positive Cancer Cells In Vitro , 2011, PloS one.

[92]  Weihong Tan,et al.  Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics , 2013, Proceedings of the National Academy of Sciences.

[93]  D. Shangguan,et al.  Development of DNA aptamers using Cell-SELEX , 2010, Nature Protocols.

[94]  Chao Liang,et al.  Molecular Selection, Modification and Development of Therapeutic Oligonucleotide Aptamers , 2016, International journal of molecular sciences.

[95]  M. Ferrari,et al.  Combinatorial selection of DNA thioaptamers targeted to the HA binding domain of human CD44. , 2010, Biochemistry.

[96]  Andrew D Ellington,et al.  Construction and selection of bead-bound combinatorial oligonucleoside phosphorothioate and phosphorodithioate aptamer libraries designed for rapid PCR-based sequencing. , 2002, Nucleic acids research.

[97]  R. Landgraf,et al.  Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[98]  Edward Chu,et al.  A history of cancer chemotherapy. , 2008, Cancer research.

[99]  M. Ferrari.  Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[100]  Zilong Zhao,et al.  Nucleic acid aptamers: an emerging frontier in cancer therapy. , 2012, Chemical communications.

[101]  Won Jong Kim,et al.  Dual-aptamer-based delivery vehicle of doxorubicin to both PSMA (+) and PSMA (-) prostate cancers. , 2011, Biomaterials.

[102]  D. Patel,et al.  Adaptive recognition by nucleic acid aptamers. , 2000, Science.

[103]  W. Duan,et al.  RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule , 2011, Cancer science.

[104]  D. Shangguan,et al.  Aptamers evolved from live cells as effective molecular probes for cancer study , 2006, Proceedings of the National Academy of Sciences.

[105]  L. Garraway,et al.  A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma , 2014, Investigational New Drugs.

[106]  Ge Zhang,et al.  Chemical Modifications of Nucleic Acid Aptamers for Therapeutic Purposes , 2017, International journal of molecular sciences.

[107]  Robert Langer,et al.  Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers , 2008, Proceedings of the National Academy of Sciences.

[108]  E. Heydari-Bafrooei,et al.  Electrochemical bioassay development for ultrasensitive aptasensing of prostate specific antigen. , 2017, Biosensors & bioelectronics.

[109]  Robert Langer,et al.  An aptamer-doxorubicin physical conjugate as a novel targeted drug-delivery platform. , 2006, Angewandte Chemie.

[110]  Yuan Zhang,et al.  Progress in Aptamer-Mediated Drug Delivery Vehicles for Cancer Targeting and Its Implications in Addressing Chemotherapeutic Challenges , 2014, Theranostics.

[111]  E. Gilboa,et al.  CD28 Aptamers as Powerful Immune Response Modulators , 2013, Molecular therapy. Nucleic acids.

[112]  J. Gariépy,et al.  Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers , 2015, Molecular therapy. Nucleic acids.

[113]  D. Drolet,et al.  An enzyme-linked oligonucleotide assay , 1996, Nature Biotechnology.

[114]  Liyu Li,et al.  Nucleolin-targeting liposomes guided by aptamer AS1411 for the delivery of siRNA for the treatment of malignant melanomas. , 2014, Biomaterials.

[115]  S. Inogés,et al.  2-fluoro-RNA oligonucleotide CD40 targeted aptamers for the control of B lymphoma and bone-marrow aplasia. , 2015, Biomaterials.

[116]  N. Janjić,et al.  Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor. , 1995, Chemistry & biology.

[117]  G. Xiong,et al.  Systemic Delivery of Anti-miRNA for Suppression of Triple Negative Breast Cancer Utilizing RNA Nanotechnology , 2015, ACS nano.

[118]  Ying Wang,et al.  Aptamer-tagged DNA origami for spatially addressable detection of aflatoxin B1. , 2017, Chemical communications.

[119]  P. Estrela,et al.  Hybrid Synthetic Receptors on MOSFET Devices for Detection of Prostate Specific Antigen in Human Plasma. , 2016, Analytical chemistry.

[120]  Xue Han,et al.  Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. , 2015, The Journal of clinical investigation.

[121]  J. McNamara,et al.  Targeting 4-1BB costimulation to disseminated tumor lesions with bi-specific oligonucleotide aptamers. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[122]  T. Hoey.  Drug Resistance, Epigenetics, and Tumor Cell Heterogeneity , 2010, Science Translational Medicine.

[123]  V. Sridharan,et al.  Plasma Membrane Nucleolin Is a Receptor for the Anticancer Aptamer AS1411 in MV4-11 Leukemia Cells , 2009, Molecular Pharmacology.

[124]  D. Bunka,et al.  Aptamers come of age – at last , 2006, Nature Reviews Microbiology.

[125]  Anil Kumar,et al.  Multifunctional aptamer-based nanoparticles for targeted drug delivery to circumvent cancer resistance. , 2016, Biomaterials.

[126]  Andrew D Ellington,et al.  Aptamer:toxin conjugates that specifically target prostate tumor cells. , 2006, Cancer research.

[127]  Tao Chen,et al.  Aptamer-conjugated nanomaterials for bioanalysis and biotechnology applications. , 2011, Nanoscale.

[128]  D. Guyer,et al.  Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease , 2006, Nature Reviews Drug Discovery.

[129]  John I. Loewenstein,et al.  Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. , 2003, Ophthalmology.

[130]  Dong-Eun Kim,et al.  RNA aptamer-conjugated liposome as an efficient anticancer drug delivery vehicle targeting cancer cells in vivo. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[131]  Y. Hoshida,et al.  Cancer biomarker discovery and validation. , 2015, Translational cancer research.

[132]  M. Ashrafuzzaman.  Aptamers as Both Drugs and Drug-Carriers , 2014, BioMed research international.

[133]  Seok Chung,et al.  An aptamer-antibody complex (oligobody) as a novel delivery platform for targeted cancer therapies. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[134]  Seonghwan Lee,et al.  Aptamers and Their Biological Applications , 2012, Sensors.

[135]  W. Duan,et al.  Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells , 2014, International journal of nanomedicine.